Numerous compounds have been reported having therapeutically and/or prophylactically useful selective COX-2 inhibitory effect, and having utility in treatment or prevention of specific COX-2 mediated disorders or of such disorders in general. Among such compounds are a large number of substituted pyrazolyl benzenesulfonamides as reported in U.S. Pat. No. 5,760,068 to Talley et al., including for example the compound 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, also referred to herein as celecoxib (I), and the compound 4-[5-(3-fluoro-4-methoxyphenyl)-3-difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, also referred to herein as deracoxib (II).

Other compounds reported to have therapeutically and/or prophylactically useful selective COX-2 inhibitory effect are substituted isoxazolyl benzenesulfonamides as reported in U.S. Pat. No. 5,633,272 to Talley et al., including the compound 4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide, also referred to herein as valdecoxib (III).

Still other compounds reported to have therapeutically and/or prophylactically useful selective COX-2 inhibitory effect are substituted (methylsulfonyl)phenyl furanones as reported in U.S. Pat. No. 5,474,995 to Ducharme et al., including the 5 compound 3-phenyl-4-[4-(methylsulfonyl)phenyl]-5H-furan-2-one, also referred to herein as rofecoxib (IV).

U.S. Pat. No. 5,981,576 to Belley et al. discloses a further series of (methylsulfonyl)phenyl furanones said to be useful as selective COX-2 inhibitory drugs, including 3-(1-cyclopropylmethoxy)-5,5-dimethyl-4-[4-(methylsulfonyl)phenyl]-5H-furan-2-one and 3-(1-cyclopropylethoxy)-5,5-dimethyl-4-[4-(methylsulfonyl)phenyl]-5H-furan-2-one.
U.S. Pat. No. 5,861,419 to Dube et al. discloses substituted pyridines said to be useful as selective COX-2 inhibitory drugs, including for example the compound 5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine (V).

European Patent Application No. 0 863 134 discloses the compound 2-(3,5-difluorophenyl)-3-[4-(methylsulfonyl)phenyl]-2-cyclopenten-1-one said to be useful as a selective COX-2 inhibitory drug.
U.S. Pat. No. 6,034,256 discloses a series of benzopyrans said to be useful as selective COX-2 inhibitory drugs, including the compound (S)-6,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid (VI).

Many selective COX-2 inhibitory drugs, including celecoxib, deracoxib, valdecoxib and rofecoxib, are hydrophobic and have low solubility in water. This has presented practical difficulties in formulating such drugs for oral administration, particularly where early onset of therapeutic effect is desired or required.
Illustratively, the formulation of celecoxib for effective oral administration to a subject has hitherto been complicated by the unique physical and chemical properties of celecoxib, particularly its low solubility and factors associated with its crystal structure, including cohesiveness, low bulk density and low compressibility. Celecoxib is unusually insoluble in aqueous media. Unformulated celecoxib is not readily dissolved and dispersed for rapid absorption in the gastrointestinal tract when administered orally, for example in capsule form. In addition, unformulated celecoxib, which has a crystal morphology that tends to form long cohesive needles, typically fuses into a monolithic mass upon compression in a tableting die. Even when blended with other substances, the celecoxib crystals tend to separate from the other substances and agglomerate together during mixing of the composition resulting in a non-uniformly blended composition containing undesirably large aggregates of celecoxib. Therefore, it is difficult to prepare a pharmaceutical composition containing celecoxib that has the desired blend uniformity. Further, handling problems arising for example from the low bulk density of celecoxib are encountered during preparation of celecoxib compositions. Accordingly, a need exists for solutions to numerous problems associated with preparation of compositions and dosage forms comprising celecoxib, particularly orally deliverable dose units.
In general, a need exists for orally deliverable formulations of a selective COX-2 inhibitory drug of low water solubility, such formulations possessing one or more of the following characteristics relative to the unformulated drug or to other compositions of the drug:                (1) improved solubility;        (2) shorter disintegration time;        (3) shorter dissolution time;        (4) decreased tablet friability;        (5) increased tablet hardness;        (6) improved wettability;        (7) improved compressibility;        (8) improved flow properties of liquid and particulate solid compositions;        (9) improved physical stability of the finished composition;        (10) reduced tablet or capsule size;        (11) improved blend uniformity;        (12) improved dose uniformity;        (13) improved control of weight variation during encapsulation and/or tableting;        (14) increased granule density for wet granulated compositions;        (15) reduced water requirement for wet granulation;        (16) reduced wet granulation time; and        (17) reduced drying time for wet granulated mixtures.        
More specifically, there exists an especial need for orally deliverable formulations of a selective COX-2 inhibitory drug of low water solubility such as celecoxib, such formulations providing both rapid onset of therapeutic effect and longer duration of therapeutic effect than the unformulated drug or known formulations of the drug. To the extent that rapid onset of therapeutic effect is related to pharmacokinetic parameters such as a high maximum blood serum concentration of the drug (Cmax) and a short time from oral administration to reach such maximum blood serum concentration (Tmax), there is an especial need for orally deliverable formulations of the drug providing a greater Cmax and/or an earlier Tmax than the unformulated drug or known formulations of the drug. At the same time, to the extent that long duration of therapeutic effect is related to pharmacokinetic parameters such as long half-life of blood serum concentration of the drug after Cmax is reached, also known as terminal half-life (T1/2), there is an especial need for orally deliverable formulations of the drug providing a longer T1/2 than the unformulated drug or known formulations of the drug. A single composition that satisfies both the need for a greater Cmax and/or an earlier Tmax and the need for a greater T1/2 would dramatically enhance the therapeutic utility of selective COX-2 inhibitory drugs in a wide variety of situations.
As is indicated hereinbelow, treatment with selective COX-2 inhibitory drugs is indicated or potentially indicated in a very wide array of COX-2 mediated conditions and disorders. It would be of benefit to provide formulations exhibiting pharmacokinetics consistent with rapid onset and long duration of therapeutic effect especially for treatment of disorders where early relief from pain or other symptoms is desired or required and where once-a-day administration is required or preferred.
Selective COX-2 inhibitory drugs including celecoxib that are of low solubility in water are conveniently formulated in solid particulate form. The individual or primary particles of the drug can dispersed in a liquid medium, as in a suspension formulation, or can be aggregated to form secondary particles or granules that can be encapsulated to provide a capsule dosage form, or compressed or molded to provide a tablet dosage form.
Numerous processes are known and used in the art for preparing drug formulations having primary particle sizes in a desired range, or having a desired mean particle size, or having a particle size distribution characterized by a parameter such as D90, which is defined herein as a linear measure of diameter having a value such that 90% by volume of particles in the formulation, in the longest dimension of the particles, are smaller than that diameter. For practical purposes a determination of D90 based on 90% by weight rather than by volume is generally suitable.
For consistency with prior publications, the terms “microparticle” and “nanoparticle” are defined herein as in U.S. Pat. No. 5,384,124 to Courteille et al., to refer to particles having respectively a diameter of between 1 μm and 2000 μm, and a diameter of less than 1 μm (1000 nm). The preparation of microparticles and nanoparticles, according to U.S. Pat. No. 5,384,124, “is principally used to retard dissolution of active principles”. However, U.S. Pat. No. 5,145,684 to Liversidge et al. discloses nanoparticulate compositions said to provide “unexpectedly high bioavailability” of drugs, particularly drugs having low solubility in a liquid medium such as water. International Publication No. WO 93/25190 provides pharmacokinetic data from a rat study indicating a higher apparent rate of absorption from oral administration of a nanoparticulate (average particle size 240–300 nm) than from oral administration of a microparticulate (particle size range 20–30 μm) dispersion of naproxen.
Illustrative processes that have been contemplated for preparing poorly water soluble drugs in nanoparticulate form are disclosed in the patents and publications listed below, each of which is individually incorporated herein by reference.
U.S. Pat. No. 4,826,689 to Violanto & Fischer.
Above-cited U.S. Pat. No. 5,145,684.
U.S. Pat. No. 5,298,262 to Na & Rajagopalan.
U.S. Pat. No. 5,302,401 to Liversidge et al.
U.S. Pat. No. 5,336,507 to Na & Rajagopalan.
U.S. Pat. No. 5,340,564 to Illig & Sarpotdar.
U.S. Pat. No. 5,346,702 to Na & Rajagopalan.
U.S. Pat. No. 5,352,459 to Hollister et al.
U.S. Pat. No. 5,354,560 to Lovrecich.
Above-cited U.S. Pat. No. 5,384,124.
U.S. Pat. No. 5,429,824 to June.
U.S. Pat. No. 5,503,723 to Ruddy et al.
U.S. Pat. No. 5,510,118 to Bosch et al.
U.S. Pat. No. 5,518,187 to Bruno et al.
U.S. Pat. No. 5,518,738 to Eickhoff et al.
U.S. Pat. No. 5,534,270 to De Castro.
U.S. Pat. No. 5,536,508 to Canal et al.
U.S. Pat. No. 5,552,160 to Liversidge et al.
U.S. Pat. No. 5,560,931 to Eickhoffet al.
U.S. Pat. No. 5,560,932 to Bagchi et al.
U.S. Pat. No. 5,565,188 to Wong et al.
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U.S. Pat. No. 5,571,536 to Eickhoffet al.
U.S. Pat. No. 5,573,783 to Desieno & Stetsko.
U.S. Pat. No. 5,580,579 to Ruddy et al.
U.S. Pat. No. 5,585,108 to Ruddy et al.
U.S. Pat. No. 5,587,143 to Wong.
U.S. Pat. No. 5,591,456 to Franson et al.
U.S. Pat. No. 5,622,938 to Wong.
U.S. Pat. No. 5,662,883 to Bagchi et al.
U.S. Pat. No. 5,665,331 to Bagchi et al.
U.S. Pat. No. 5,718,919 to Ruddy et al.
U.S. Pat. No. 5,747,001 to Wiedmann et al.
Above-cited International Patent Publication No. WO 93/25190.
International Patent Publication No. WO 96/24336.
International Patent Publication No. WO 97/14407.
International Patent Publication No. WO 98/35666.
International Patent Publication No. WO 99/65469.
International Patent Publication No. WO 00/18374.
International Patent Publication No. WO 00/27369.
International Patent Publication No. WO 00/30615.
Alternatively, drugs of low water solubility have sometimes been formulated in solution in a pharmaceutically acceptable solvent such as polyethylene glycol. Solution formulations typically permit rapid absorption of the dissolved drug, in some cases giving even more rapid onset of therapeutic effect than is possible with nanoparticulate formulations.
Solutions and suspensions of nanoparticles and/or microparticles can be formulated as liquid dosage forms, the required dose being measured, for example using a cup, at the time of administration. Alternatively, solutions and suspensions can be formulated as flowable liquids or as gels in unit dose articles such as sachets or soft capsules. Sachets are opened and only the contents administered orally to the subject; soft capsules are a more convenient dosage form as the entire capsule is orally administered. Typically soft capsule walls are composed predominantly of gelatin and the terms “softgel” or “gelcap” are sometimes used to describe these formulations.
Anti-inflammatory, antipyretic and analgesic drugs, for example nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids have not frequently been formulated as rapid-release solutions, gels or soft capsules for oral administration. However, illustrative processes for preparing such formulations are disclosed in the patents and publications listed below, each of which is individually incorporated herein by reference.
U.S. Pat. No. 5,859,060 to Platt.
European Patent Application No. 0 945 131.
Japanese Laid-Open Patent Application No. 03/106815.
Extending the half-life of an orally administered drug is achievable by a variety of controlled-release, slow-release, programmed-release, timed-release, pulse-release, sustained-release or extended-release technologies known in the art. Typically such technologies involve formulating the drug in a polymer matrix from which the drug is gradually released, or protecting the drug from immediate release by means of a barrier layer which degrades over time in the gastrointestinal tract. Examples of barrier layers include liposomes, nanocapsules, microcapsules and coatings on granules, beads or tablets. Dosage forms can be liquids (e.g., suspensions) or unit dose articles (e.g., tablets, capsules, soft capsules).
Illustrative processes that have been contemplated for preparing controlled-release, slow-release, programmed-release, timed-release, pulse-release, sustained-release or extended-release formulations of opioids, NSAIDs and other analgesic, antipyretic and anti-inflammatory drugs are disclosed in the patents and publications listed below, each of which is individually incorporated herein by reference.
U.S. Pat. No. 3,362,880 to Jeffries.
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International Patent Publication No. WO 87/00044.
International Patent Publication No. WO 89/08119.
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International Patent Publication No. WO 93/10760.
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International Patent Publication No. WO 96/16638.
International Patent Publication No. WO 98/01117.
International Patent Publication No. WO 99/12524.
International Patent Publication No. WO 99/51209.
International Patent Publication No. WO 99/61005.
Belgian Patent Application No. 900 824.
European Patent Application No. 0 147 780.
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European Patent Application No. 0 516 141.
European Patent Application No. 0 875 245.
European Patent Application No. 0 945 137.
French Patent Application No. 2 584 604.
Japanese Laid-Open Patent Application No. 56/030402.
Japanese Laid-Open Patent Application No. 60/072,813.
Japanese Laid-Open Patent Application No. 63/174925.
Japanese Laid-Open patent application Ser. No. 10/298,064.
Attempts have been made to formulate certain NSAIDs, opioids or other analgesic, antipyretic or anti-inflammatory drugs in single dual-release compositions having both an immediate-release fraction and a controlled-release, slow-release, programmed-release, timed-release, pulse-release, sustained-release or extended-release fraction of the drug. Such compositions have been disclosed, for example, for NSAIDs generally in the patents and publications listed below, each of which is individually incorporated herein by reference.
U.S. Pat. No. 4,980,170 to Schneider et al.
International Publication No. WO 99/12524.
Such dual-release compositions have illustratively been disclosed for ibuprofen in the patents and publications listed below, each of which is individually incorporated herein by reference.
U.S. Pat. No. 5,681,583 to Conte et al.
International Publication No. WO 96/41617.
Such dual-release compositions have illustratively been disclosed for naproxen in the patents listed below, each of which is individually incorporated herein by reference.
U.S. Pat. No. 4,888,178 to Rotini & Marchi.
U.S. Pat. No. 5,609,884 to Desai.
Several factors influence dissolution in a solvent medium of a drug from its carrier, including the surface area of the drug presented to the solvent medium, the solubility of the drug in the solvent medium, and the driving forces of the saturation concentration of dissolved materials in the solvent medium. Notwithstanding these factors, a strong correlation has been established between the in vitro dissolution time determined for a dosage form and the in vivo drug release rate. This correlation is so firmly established in the art that dissolution time has become generally descriptive of drug release potential for the active component of the particular unit dosage composition. In view of this relationship, it is clear that dissolution time determined for a composition is one of the important fundamental characteristics for consideration when evaluating dual-release compositions.
Selective COX-2 inhibitory drugs have not previously been formulated in dual-release dosage forms. Certain drugs of this class have a sufficiently long half-life, even when conventionally formulated for oral delivery, to be suitable for once-a-day administration. For example, Canadian Patent Application No. 2,254,061 discloses that rofecoxib has a half-life sufficient to provide therapeutic benefit over a 24-hour period.